Small intestine intraepithelial lymphocytes (IELs) comprise a heterogeneous and phenotypically complex population of T cells that are part of the gut-associated lymphoid tissues (GALTs). Recent studies from a number of laboratories indicate that murine IELs are greatly enriched for extrathymic T cells, although many aspects of the IEL+ extrathymic developmental pathway remain controversial, and there is currently no consensus of opinion as to which IELs are extrathymic and which are thymus-derived. Those differences reflect variations in the IEL repertoire in athymic animals depending upon the specific model used to study IELs, and they correlate with the age at which mice became or were rendered athymic, implying that the thymus participates either directly or indirectly in the local extrathymic IEL developmental process. In this article, the basic findings regarding intestinal T cell development are discussed, and a hypothesis is provided which links neuroendocrine interactions targeted to the intestine epithelium to the striking relationship between animal developmental age and the thymopoietic potential of the intestine.
Schistosomiasis is a parasitic disease in which focal inflammatory responses called granulomas develop in the liver and intestines. The inflammatory cells within these granulomas produce authentic vasoactive intestine peptide (VIP). VIP acts as an immune modulator. In the schistosome granuloma, VIP can suppress T cell proliferation and T lymphocyte IL-2 production. Also, it can enhance IL-5 production from granuloma T cells. The granuloma T cells bear authentic VIP receptors of both the VIPr1 and VIPr2 subclasses. It is probable that the expression of these receptors is subject to immunoregulation, which is the topic of current investigation. Moreover, differences in the structure of VIPr1 and VIPr2 suggest that each may have unique immunoregulatory functions in inflammation.
The aim of this clinical review is to highlight recent advances in immunology, as well as new information from selected other areas, which have led to a better appreciation of the neuroimmunologic mechanisms involved in Multiple sclerosis (MS). New data on immunopathology, the cytokine network, and the role of oligodendrocytes, lymphocytes, and endothelial cells in this disease, have produced novel therapeutic approaches. New information on clinical course and neuroimaging disease features, as well as the role of genetic factors and infectious agents, have also improved our understanding of the immune basis for MS.
The belief that cancer might be related to temperament or distress has been emphasized throughout the history of medicine. The field of psychoneuroimmunology has its origins in psychosomatic medicine, and has evolved to the investigations of complex interactions between the psyche and the nervous, immune, and endocrine systems. Such interactions may have implications in both cancer risk and survival.
Our previous studies have shown that prolactin (PRL), a pituitary and lymphocyte hormone and a ligand of the cytokine/hemopoietin receptors (R) superfamily, acts synergistically with interleukin (IL)-2 on the development of lymphokine activated killer (LAK) cells and enhances the effects of GM-CSF and IL-3 on myeloid progenitors' proliferation and differentiation. More recently, we have demonstrated that GM-CSF and IL-3 increase the sensitivity of acute myeloid leukemic (AML) cells to LAK activity. Together, these findings have prompted us to study the role of PRL on the target arm of the LAK response. We show here that CD33+ blasts from AML patients express membrane PRL-R and that the PRL/PRL-R interaction is followed by increased susceptibility to natural killer (NK) (p < 0.02) and LAK (p < 0.001) cells. As predicted from the dimerization model of PRL-R and in agreement with previous reports, the response of AML blasts to PRL was bell-shaped with a trend peak at 25 ng/ml. Although enhanced lysis occurred at the target recognition level, it was not accompanied by changes in the MHC class I, cellular adhesion molecules, or myeloid differentiation antigens. Cell cycle recruitment and lysis increased concurrently in three cases studied, suggesting a modulatory action of PRL on the expression of putative cycle-related NK/LAK-target structures. Together, these data strengthen the role of PRL in the LAK response.
Clinical research has focused on autoimmune disease (AID) for a couple of decades. More sensitive and specific methods have been developed for neuroimmunological research. Gamma fraction bands (bands separated by electrophoresis and visualized by amino black staining) and IgG fraction bands (bands separated by iso-electric focusing and visualized by immunostaining) are used instead of oligoclonal bands. Myasthenia gravis (MG) mainly involves acetylcholine receptors of the postsynaptic membrane at the neuromuscular junction. Myasthenia gravis has been considered to be a generalized AID, because 7% of patients with myasthenia gravis associate with other AIDs and more than one autoimmune antibody is detected in 52.5% patients with myasthenia gravis. Pyramidal signs in myasthenia gravis patients are described; the possible mechanism may at least be partly due to the acetylcholine receptor antibody. P2 protein and its antibody are studied in patients with acute and chronic inflammatory demyelinating polyneuropathy.
The effects of vasoactive intestinal peptide (VIP) on human immunoglobulin (Ig) production were studied in (1) B cell lines; (2) anti-CD40 mAb-stimulated B cells from non-atopic donors; and (3) unstimulated mononuclear cells from atopic patients. In B cell lines, GM-1056, IM-9, and CBL, VIP enhanced IgA1, IgG1 and IgM production, respectively, in a dose-dependent fashion, while the other neuropeptides somatostatin (SOM) or substance P (SP) failed to do so. Among the various cytokines examined including IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, and G-CSF, IL-6 and IL-10 also enhanced Ig production. However, VIP-induced enhancement of Ig production was specific, and was not mediated via these cytokines, since enhancement was blocked by the VIP antagonist, while SOM and SP antagonists, anti-IL-6 mAb, or anti-IL-10 Ab failed to do so. In anti-CD40 mAb-stimulated B cells from non-atopic donors, VIP selectively induced IgA1 and IgA2 production without affecting IgG1, IgG2, IgG3, IgG4, IgM, or IgE production. This stimulatory effect was specifically blocked by the VIP antagonist, but not by SOM or SP antagonists, anti-IL-5 mAb, anti-IL-10 Ab, or anti-TGF-β Ab. VIP induced IgA1 and IgA2 production by surface IgA1− (sIgA1−) and sIgA2− B cells, respectively, while this agent had no effect on sIgA1+ and sIgA2+ B cells. In contrast, in unstimulated mononuclear cells from atopic patients, VIP selectively inhibited spontaneous IgE and IgG4 production without affecting IgG1, IgG2, IgG3, IgM, IgA1, or IgA2 production. This inhibitory effect was specifically blocked by the VIP antagonist, but not by anti-IFN-α Ab, anti-IFN-γ mAb, anti-IL-12 Ab, or anti-TGF-β Ab. VIP did not inhibit IgE or IgG4 production in B cells or in B cells cultured with either T cells or monocytes. However, VIP inhibited IgE and IgG4 production when B cells were cultured with both T cells and monocytes.
The hyt/hyt mouse has an autosomal recessive, fetal onset, characterized by severe hypothyroidism that persists throughout life and is a reliable model of human sporadic congenital hypothyroidism. The hypothyroidism in the hyt/hyt mouse reflects the hyporesponsiveness of the thyroid gland to thyrotropin (TSH). This is attributable to a point mutation of C to T at nucleotide position 1666, resulting in the replacement of a Pro with Leu at position 556 in transmembrane domain IV of the G protein-linked TSH receptor. This mutation leads to a reduction in all CAMP-regulated events, including thyroid hormone synthesis. The diminution in T3/T4 in serum and other organs, including the brain, also leads to alterations in the level and timing of expression of critical brain molecules, i.e. selected tubulin isoforms (Mβ5, Mβ2, and Mα1), microtubule associated proteins (MAPS), and myelin basic protein, as well as to changes in important neuronal cytoskeletal events, i.e. microtubule assembly and SCa and SCb axonal transport. In the hyt/hyt mouse, fetal hypothyroidism leads to reductions in Mβ5, Mβ2, and Mα1 mRNAs, important tubulin isoforms, and Mβ5 and Mβ2 proteins, which comprise the microtubules. These molecules are localized to layer V pyramidal neurons in the sensorimotor cortex, a site of differentiating neurons, as well as a site for localization of specific thyroid hormone receptors. These molecular abnormalities in specific cells and at specific times of development or maturation may contribute to the observed neuroanatomical abnormalities, i.e. altered neuronal process growth and maintenance, synaptogenesis, and myelination, in hypothyroid brain. Abnormal neuroanatomical development in selected brain regions may be the factor underlying the abnormalities in reflexive, locomotor, and adaptive behavior seen in the hyt/hyt mouse and other hypothyroid animals.
The nervous and endocrine systems modulate the immune system functions through releasing neurotransmitters, neuropeptides and endocrine hormones as they regulate the other physiological functions. The immune system in turn communicates with the nervous and endocrine systems through secreting immunocompetent substances. In this report we review our concepts and evidence concerning the immunoregulatory role of acetylcholine (ACh) and monoamine neurotransmitters which include noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA). The immunoregulatory role comprises two aspects, the modulation of immune functions by neurotransmitters and the effect of the immune system on nervous system functions. The inhibition of ACh biosynthesis in the central nervous system (CNS) caused the enhancement of the humoral immune response of rats to sheep red blood cells (SRBC); by contrast, the inhibition of acetylcholinesterase (AChE) activity in the CNS resulted in the suppression of the immune response. It seems that ACh in the brain plays an immunoinhibitory role. The role can be blocked by atropine, a muscarinic antagonist, but not by hexamethonium, a nicotinic antagonist. During the humoral immune response (days 3–6 after SRBC injection), activity of AChE in the hypothalamus and hippocampus was strikingly lower. It is suggested that a functional connection is present in the ACh of the brain and the immune system. In vitro, ACh at 10−9 to 10−4 mol/l dose range significantly strengthened the spleen cell proliferation induced by concanavalin (Con A). The action of ACh only occurred either before or just after T lymphocytes were activated through muscarinic cholinergic receptors. In vivo, the depletion of monoamine neurotransmitters or only NA in the CNS caused the impairment of the anti-SRBC response of rats. During the phases of days 2–7 post-immunization, the metabolic alterations of NA, 5-HT and DA emerged in the CNS and the lymphoid organs of rats, which mainly exhibited that in the peak periods of the antibody response, the metabolism of the monoamine neurotransmitters in the hypothalamus and hippocampus was markedly increased, but NA content in the spleen and thymus was significantly decreased. These results provide evidence for the bidirectional information exchange network between the monoamine neurotransmitters and the immune system. Exposure to NA (at 10−8–10−5 mol/l concentration range) in vitro was shown to inhibit the Con A-induced proliferation of the rat spleen cells. This effect of NA was related to the early events involved in the initiation of T cell proliferation and was mediated by either alpha- or beta- adrenergic receptors. The evidence that altering 5-HT level in the central or peripheral nervous systems through various ways of administering the drugs to regulate 5-HT biosynthesis led to the variations of the antibody response, and that cyproheptadine, an antagonist of serotoninergic receptors, can block the action of 5-HT show that 5-HT may exert an immunoinhibitory effect, which appears to be mediated via the peripheral mechanism to relate to the 5-HT receptors. However, the antibody response can cause changes in 5-HT metabolism in the CNS. The possible reasons for these results are discussed. Collectively, the antibody response arouses the metabolic variations of ACh, NA, 5-HT and DA in the central and peripheral nervous systems and then, these alterations can in turn influence immune function through neurotransmitter relevant receptors present on the immunocytes. The purpose of this interaction is most likely to maintain the homeostasis of the immune and other physiological functions.
The role of classical neurotransmitters in sleep regulation is amply documented (Hobson and Steriade, 1986). In recent years evidence has been gathered that immunoactive molecules, infectious agents and their components, or cytokines play some part in sleep regulation (Krueger and Obál, 1994; Opp et al., 1992; Moldofsky, 1994). Different cytokines possess hypnogenic properties when injected centrally or systemically to different animal species and their role in physiological sleep regulation is currently under investigation. Little is known of how cytokines and classical neurotransmitters interact and of the relevance of this interaction in sleep induction and maintenance. The present paper (i) reviews data on this topic; (ii) proposes a unitary interpretation whenever possible; and (iii) raises questions that might be addressed by future studies.
The aim of this review is to provide a comprehensive examination of the current literature describing the immunoregulatory effects on the peripheral immune system by the hormones that comprise the hypothalamic-pituitary-thyroid (HPT) axis. This article discusses the effects of the HPT axis hormones on the peripheral lymphoid tissues and the immune responses mediated by the cells that comprise these lymphoid tissues. Neuroendocrine dysfunction in the HPT axis, either naturally or experimentally induced, and the resulting immune dysfunction are also discussed. Emphasis in this article is placed on the most recent study findings and those that provide a unique or novel way of evaluating HPT hormone effects on the immune system. Our knowledge of the immunoregulatory effects of the hormones that comprise the HPT axis has grown tremendously in the last 10 years. As can be seen in this review, the immunoregulatory effects of the HPT axis hormones are quite diverse and influence most, if not all, aspects of immune system physiology. The continued exploration of the bidirectional circuitry between the immune and neuroendocrine systems may allow for development of appropriate prophylactic procedures that prevent dysfunction in both systems.
Nitric oxide, in recent years, has emerged as an important substance capable of modifying many biological processes. It is involved with both neural and immune processes. In my laboratory I will be examining the relationship of nitric oxide and its involvement with modifying dopaminergic processes. In this review, I examine reports that already document this relationship. Nitric oxide appears to be able to facilitate the release of various monoamines, especially dopamine. Furthermore, this gas has the ability to block the presynaptic re-uptake of dopamine as well. Taken together, it would appear that nitric oxide can prolong the 'life' of dopamine in the synapse. Given the significance of dopamine in motor and psychological processes the significance of nitric oxide involvement increases exponentially.
Neuropeptides have recently been shown to modulate the immune response. Vasoactive intestinal peptide (VIP) released from nerve endings and from immune cells modulates the mobility and adherence of lymphocytes and macrophages, phagocytic cell functions (phagocytosis and free radical production), the lymphocyte proliferative response, lymphokine and immunoglobulin production and the natural killer cell activity, with opposite effects in vitro on these immune cell functions. The VIP receptor heterogeneity and the different action mechanisms of VIP-mediated immunoregulation could explain, at least in part, the different VIP effects observed on lymphoid and phagocytic cells. The evidence supports the theory that VIP acts not as an inhibitor, but as a modulator of immune functions, as previously thought, and that this neuropeptide may play a relevant role in vivo.
Evidence for VIP influences on immune function comes from studies demonstrating VIP-ir nerves in lymphoid organs in intimate anatomical association with elements of the immune system, the presence of high-affinity receptors for VIP, and functional studies where VIP influences a variety of immune responses. Anatomical studies that examine the relationship between VIP-containing nerves and subpopulations of immune effector cells provide evidence for potential target cells. Additionally, the presence of VIP in cells of the immune system that also possess VIP receptors implies an autocrine function for VIP. The functional significance of VIP effects on the immune system lies in its ability to help coordinate a complex array of cellular and subcellular events, including events that occur in lymphoid compartments, and in musculature and intramural blood circulation. Clearly, from the work described in this chapter, the modulatory role of VIP in immune regulation is not well understood. The pathways through which VIP can exert an immunoregulatory role are complex and highly sensitive to physiological conditions, emphasizing the importance of in vivo studies. Intracellular events following activation of VIP receptors also are not well elucidated. There is additional evidence to suggest that some of the effects of VIP on cells of the immune system are not mediated through binding of VIP to its receptor. Despite our lack of knowledge regarding VIP immune regulation, the evidence is overwhelming that VIP can interact directly with lymphocytes and accessory cells, resulting in most cases, but not always in cAMP generation within these cells, and a subsequent cascade of intracellular events that alter effector cell function. VIP appears to modulate maturation of specific populations of effector cells, T cell recognition, antibody production, and homing capabilities. These effects of VIP are tissue-specific and are probably dependent on the resident cell populations within the lymphoid tissue and the surrounding microenvironment. Different microenvironments within the same lymphoid tissue may influence the modulatory role of VIP also. Effects of VIP on immune function may result from indirect effects on secretory cells, endothelial cells, and smooth muscle cells in blood vessels, ducts, and respiratory airways. Influences of VIP on immune function also may vary depending on the presence of other signal molecules, such that VIP alone will have no effect on a target cell by itself, but may greatly potentiate or inhibit the effects of other hormones, transmitters, or cytokines. The activational state of target cells may influence VIP receptor expression in these cells, and therefore, may determine whether VIP can influence target cell activity. Several reports described in this chapter also indicate that VIP contained in neural compartments is involved in the pathophysiology of several disease states in the gut and lung. Release of inflammatory mediators by cells of the immune system may destroy VIP-containing nerves in inflammatory bowel disease and in asthma. Loss of VIPergic nerves in these disease states appears to further exacerbate the inflammatory response. These studies indicate that altered VIP concentration can have significant consequences in terms of health and disease. In addition, the protective effects of VIP from tissue damage associated with inflammatory processes described in the lung also may be applicable to other pathological conditions such as rheumatoid arthritis, anaphylaxis, and the swelling and edema seen in the brain following head trauma. While VIP degrades rapidly, synthetic VIP-like drugs may be developed that interact with VIP receptors and have similar protective effects. Synthetic VIP-like agents also may be useful in treating neuroendocrine disorders associated with dysregulation of the hypothalamic-pituitary-adrenal axis, and pituitary release of prolactin.
In the last few decades, as a result of the interaction between different areas of research, the new interdisciplinary and exciting field of neuroimmunology has emerged. In this context, it has been demonstrated that small peptides may function in a communication network that links nervous, endocrine, and immune systems. Thus, each peptide may function as a neurotransmitter, peptide hormone, or cytokine, depending on its site of release and the target cell with which it interacts. Among these peptides, vasoactive intestinal peptide (VIP) has been shown to play a very important role in the regulation of immune function. The first stage in the action of VIP with immunocompetent cells is the binding to specific plasma membrane receptors and the generation of an intracellular signal. In this review, we focus and present data about the signal transduction pathway of VIP in both human and rodent immunocompetent cells.
Thyroid disorders are the most common endocrine diseases and affect a large segment of the population. Most of the thyroid diseases are autoimmune in nature and can be broadly grouped into two categories; one mediated by autoimmune responses to the thyroglobulin (i.e. Hashimoto's thyroiditis), and the other mediated by autoimmunity to the thyrotropin receptor (primarily Graves' disease). Although patients with autoimmune thyroid diseases exhibit immune responses against a number of thyroid antigens, such as thyroglobulin, thyrotropin receptor and thyroid peroxidase, responses directed against a specific antigen appear to play an important role in the disease pathogenesis. For example, Hashimoto's thyroiditis is primarily mediated by T cell responses directed toward the thyroglobulin receptor, whereas Graves' disease is mediated by antibodies directed against the thyrotropin receptor. In this review we will focus on thyroid diseases mediated by autoimmune responses tothethyrotropinreceptor.
Recent evidence indicates that the neuroendocrine and immune systems are intimately integrated into one system that provides a complex homeostatic network. Disruption of one system by extrinsic factors such as stress or antigenic exposure usually has consequences on the other. With advancing age, a progressive disruption can be observed in both systems which may have profound implications with respect to age-associated pathologies, including autoimmunity. In this review evidence is summarized which supports the hypothesis that neuroendocrine factors influence the age-associated decline of the immune system.
Microglial cells are brain macrophages which serve specific functions in the defense of the central nervous system (CNS) against microorganisms, the removal of tissue debris in neurodegenerative diseases or during normal development, and in autoimmune inflammatory disorders of the brain. In cultured microglial cells, several soluble inflammatory mediators such as cytokines and bacterial products like lipopolysaccharide (LPS) were demonstrated to induce a wide range of microglial activities, e.g. increased phagocytosis, chemotaxis, secretion of cytokines, activation of the respiratory burst and induction of nitric oxide synthase. Since heightened microglial activation was shown to play a role in the pathogenesis of experimental inflammatory CNS disorders, understanding the molecular mechanisms of microglial activation may lead to new treatment strategies for neurodegenerative disorders, multiple sclerosis and bacterial or viral infections of the nervous system.
The aim of the review is to summarize our recent studies on the influence of the thymus on liver functions and its intermediary pathway in rats. Young adult thymectomized rats were used as a model in the experiments, and either thymic peptides or sex hormones were supplemented to these animals. Liver microsomal cytochrome P-450 and aminopyrine-N-demethylase (ADM) activities were decreased in thymectomized rats, and the change in the male was more significant than that in female rats. An increase of liver malondialdehyde (MDA) and a decrease of liver glutathione (GSH) and superoxide dismutase activity were observed in the female thymectomized rats, but not in the males. Accompanied by the increase of MDA, a decline of membrane fluidity of liver microsomes and mitochondria and a decrease of Ca2+ uptake by liver microsomes were exhibited in the female thymectomized rats. Subcutaneous injection of thymic peptides decreased MDA level, and increased GSH content, membrane fluidity and Ca2+ uptake by microsomes in the liver of thymectomized rats. On the other hand, male thymectomized rats showed a decrease of hypothalamic luteinizing hormone-releasing hormone (LHRH), plasma luteinizing hormone (LH) and testosterone levels. Subcutaneous injection of testosterone propionate to these animals restored their liver P-450 and ADM activities to normal levels. Female thymectomized rats exhibited a decline of hypothalamic LHRH and plasma estradiol levels. Supplementation of estradiol benzoate reversed the increase of liver MDA in these animals. The data suggest that the thymus may influence liver functions through the hypothalamus-pituitary-gonad axis. Thus, a new ‘thymus-neuroendocrine-liver pathway’ is proposed, which may account for the significance of the thymus in maintaining homeostasis and integrative functions in the body.
